Prognostic Impact of miR-224 and RAS Mutations in Medullary Thyroid Carcinoma

Little is known about the function of microRNA-224 (miR-224) in medullary thyroid cancer (MTC). This study investigated the role of miR-224 expression in MTC and correlated it with mutation status in sporadic MTCs. A consecutive series of 134 MTCs were considered. Patients had a sporadic form in 80% of cases (107/134). In this group, REarranged during transfection (RET) and rat sarcoma (RAS) mutation status were assessed by direct sequencing in the tumor tissues. Quantitative real-time polymerase chain reaction was used to quantify mature hsa-miR-224 in tumor tissue. RAS (10/107 cases, 9%) and RET (39/107 cases, 36%) mutations were mutually exclusive in sporadic cases. miR-224 expression was significantly downregulated in patients with the following: high calcitonin levels at diagnosis (p=0.03, r=−0.3); advanced stage (p=0.001); persistent disease (p=0.001); progressive disease (p=0.002); and disease-related death (p=0.0001). We found a significant positive correlation between miR-224 expression and somatic RAS mutations (p=0.007). Patients whose MTCs had a low miR-224 expression tended to have a shorter overall survival (log-rank test p=0.005). On multivariate analysis, miR-224 represented an independent prognostic marker. Our data indicate that miR-224 is upregulated in RAS-mutated MTCs and in patients with a better prognosis and could represent an independent prognostic marker in MTC patients

Frequency and significance of Ras, Tert promoter, and Braf mutations in cytologically indeterminate thyroid nodules: A monocentric case series at a tertiary-level Endocrinology unit

PurposeThe management of thyroid nodules of indeterminate cytology is controversial. Our study aimed to establish the frequency and significance of H-,K-,N-RAS, TERT promoter, and BRAF gene mutations in thyroid nodes of indeterminate cytology and to assess their potential usefulness in clinical practice.MethodsH-,K-,N-RAS, TERT promoter and BRAF gene mutations were examined in a series of 199 consecutive nodes of indeterminate cytology referred for surgical excision.Results69/199 (35%) were malignant on histopathological review. RAS mutations were detected in 36/199 (18%), and 19/36 cases (53%) were malignant on histological diagnosis. TERT promoter mutations were detected in 7/199 (4%) nodules, which were all malignant lesions. BRAF mutations were detected in 15/199 (8%), and a BRAF K601E mutation was identified in 2 follicular adenomas and 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Altogether, this panel was able to identify 48% of the malignant lesions, achieving a specificity, positive predictive value, and negative predictive value for malignancy of 85, 62, and 75%, respectively.ConclusionThe residual malignancy risk in mutation-negative nodes is 25%. These nodes still need to be resected, but mutation analysis could help to orient the appropriate surgical strategy

A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAF(V600E) may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice

PROGNOSTIC SIGNIFICANCE OF TERT PROMOTER AND BRAF MUTATIONS IN TIR-4 AND TIR-5 THYROID CYTOLOGY

Objective: Follicular-derived thyroid cancers generally have a good prognosis, but in a minority of cases, they have an aggressive behavior and develop distant metastases, with an increase in the associated mortality. None of the prognostic markers currently available prior to surgery can identify such cases. Methods: TERT promoter and BRAF gene mutations were examined in a series of 436 consecutive TIR-4 and TIR-5 nodes referred for surgery. Follow-up (median: 59 months, range: 7-293 months) was available for 384/423 patients with malignant nodes. Results: TERT promoter and BRAF mutations were detected in 20/436 (4.6%) and 257/434 thyroid nodules (59.2%), respectively. At the end of the follow-up, 318/384 patients (82.8%) had an excellent outcome, 48/384 (12.5%) had indeterminate response or biochemical persistence, 18/384 (4.7%) had a structural persistence or died from thyroid cancer. TERT promoter mutations correlated with older age (P < 0.0001), larger tumor size (P = 0.0002), oxyntic and aggressive PTC variants (P = 0.01), higher tumor stages (P < 0.0001), distant metastases (<0.0001) and disease outcome (P < 0.0001). At multivariate analysis, TERT promoter mutation was not an independent predictor of disease outcome. TERT promoter mutation- (OR: 40.58; 95% CI: 3.06-539.04), and N1b lymph node metastases (OR: 40.16, 95% CI: 3.48-463.04) were independent predictors of distant metastases. BRAF mutation did not predict the outcome, and it correlated with a lower incidence of distant metastases (P = 0.0201). Conclusions: TERT promoter mutation proved an independent predictor of distant metastases, giving clinicians the chance to identify many of the patients who warranted more aggressive initial treatment and closer follow-up

Pai Hsien-yung, Crystal Boys and Taipei's Memories : View from 'Metropolis Spaces' of the 1970s(Summaries : International Symposium "People's Transportation and Cultural Diversity in East Asia")

Genetic signatures from the Paleolithic inhabitants of Eurasia can be traced from the early divergent mitochondrial DNA lineages still present in contemporary human populations. Previous studies already suggested a pre-Neolithic diffusion of mitochondrial haplogroup HV*(xH,V) lineages, a relatively rare class of mtDNA types that includes parallel branches mainly distributed across Europe and West Asia with a certain degree of structure. Up till now, variation within haplogroup HV was addressed mainly by analyzing sequence data from the mtDNA control region, except for specific sub-branches, such as HV4 or the widely distributed haplogroups H and V. In this study, we present a revised HV topology based on full mtDNA genome data, and we include a comprehensive dataset consisting of 316 complete mtDNA sequences including 60 new samples from the Italian peninsula, a previously underrepresented geographic area. We highlight points of instability in the particular topology of this haplogroup, reconstructed with BEAST-generated trees and networks. We also confirm a major lineage expansion that probably followed the Late Glacial Maximum and preceded Neolithic population movements. We finally observe that Italy harbors a reservoir of mtDNA diversity, with deep-rooting HV lineages often related to sequences present in the Caucasus and the Middle East. The resulting hypothesis of a glacial refugium in Southern Italy has implications for the understanding of late Paleolithic population movements and is discussed within the archaeological cultural shifts occurred over the entire continent

BRAF V600E Status Sharply Differentiates Lymph Node Metastasis-associated Mortality Risk in Papillary Thyroid Cancer

[Context]: How lymph node metastasis (LNM)-associated mortality risk is affected by BRAF V600E in papillary thyroid cancer (PTC) remains undefined. [Objective]: To study whether BRAF V600E affected LNM-associated mortality in PTC. [Design, Setting, and Participants]: We retrospectively analyzed the effect of LNM on PTC-specific mortality with respect to BRAF status in 2638 patients (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 [interquartile range (IQR) 35-58] years and median follow-up time of 58 (IQR 26-107) months. [Results]: Overall, LNM showed a modest mortality risk in wild-type BRAF patients but a strong one in BRAF V600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAF V600E patients; mortality rates were 2/659 (0.3%) vs 4/321 (1.2%) in non-LNM vs LNM patients (P = 0.094) with wild-type BRAF, corresponding to a hazard ratio (HR) (95% CI) of 4.37 (0.80-23.89), which remained insignificant at 3.32 (0.52-21.14) after multivariate adjustment. In BRAF V600E CPTC, morality rates were 7/515 (1.4%) vs 28/363 (7.7%) in non-LNM vs LNM patients (P < 0.001), corresponding to an HR of 4.90 (2.12-11.29) or, after multivariate adjustment, 5.76 (2.19-15.11). Adjusted mortality HR of coexisting LNM and BRAF V600E vs absence of both was 27.39 (5.15-145.80), with Kaplan-Meier analyses showing a similar synergism. [Conclusions]: LNM-associated mortality risk is sharply differentiated by the BRAF status in PTC; in CPTC, LNM showed no increased mortality risk with wild-type BRAF but a robust one with BRAF mutation. These results have strong clinical relevance.This work was supported partly by the following funding at the individual participating centers: Polish National Center of Research and Development MILESTONE Project—molecular diagnostics and imaging in individualized therapy for breast, thyroid and prostate cancer, grant No. STRATEGMED2/267398/4/ NCBR/2015 (Poland, AC, BJ); Grants No. PID2019-105303RB-I00 (AEI from MICINN), GCB14142311CRES (AECC Foundation), and B2017/BMD-3724 TIRONET2-CM (Spain; PS and GR-E); Grant No. AZV 16-32665A and MH CZ-DRO (Institute of Endocrinology-EU, 00023761) (Czech Republic; BB, VS); NIH/ National Institute on Aging Grant No. 5R03AG042334-02 (LY); and grants from the Qingdao Science and Technology Project for People’s Livelihood No.13-1-3-58-nsh (China; FW) and the Innovative Platform Project of Qingdao No.12-1-2-15-jch (China; YW)

Re-evaluation of neohesperidine dihydrochalcone (E 959) as a food additive

The present opinion deals with the re-evaluation of neohesperidine dihydrochalcone (E 959) when used as a food additive. It is obtained by catalytic hydrogenation of a flavanone - neohesperidine - which is naturally occurring and thus isolated by alcohol extraction in bitter oranges (Citrus aurantium). Based on in vivo data in rat, neohesperidine dihydrochalcone is likely to be absorbed, also in humans, and to become systemically available. It does not raise a concern regarding genotoxicity. The toxicity data set consisted of studies on subchronic and prenatal developmental toxicity. No human studies were available. The data set was considered sufficient to derive a new acceptable daily intake (ADI). Based on the weight of evidence (WoE) analysis, the Panel considered unlikely that neohesperidine dihydrochalcone would lead to adverse effects on health in animals in the dose ranges tested. The Panel also considered that a carcinogenicity study was not warranted and that the lack of human data did not affect the overall confidence in the body of evidence. The Panel derived an ADI of 20 mg/kg bodyweight (bw) per day based on a no observed adverse effect level (NOAEL) of 4,000 mg/kg bw per day from a 13-week study in rat, applying the standard default factors of 100 for inter- and intraspecies differences and of 2 for extrapolation from subchronic to chronic exposure. For the refined brand-loyal exposure assessment scenario, considered to be the most appropriate for the risk assessment, the exposure estimates at the mean ranged from < 0.01 to 0.09 mg/kg bw per day and at the 95th percentile (P95) from 0.01 to 0.24 mg/kg bw per day. Considering the derived ADI of 20 mg/kg bw per day, the exposure estimates were below the reference value in all age groups. Therefore, the Panel concluded that dietary exposure to the food additive neohesperidine dihydrochalcone (E 959) at the reported uses and use levels would not raise a safety concern

Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS)

Dysregulated systemic inflammation is the primary driver of mortality in severe COVID-19 pneumonia. Current guidelines favor a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg·day-1. A comparative RCT with a higher dose and a longer duration of intervention was lacking

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score &gt; 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p &lt; 0.001), RR = 2.19 for ICU admission (p &lt; 0.001), and RR = 2.43 for death (p &lt; 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon